Approved drugs and natural products at clinical stages for treating Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) remains the foremost cause of dementia and represents a significant unmet healthcare need globally. The complex pathogenesis of AD, characterized by various pathological and physiological events, has historically challenged the development of anti-AD drugs. However, recent breakthroughs in AD drug development, including the approvals of aducanumab, lecanemab, and sodium oligomannate (GV-971), have ended a nearly two-decade hiatus in the introduction of new AD drugs. These developments have addressed long-standing challenges in AD drug development, marking a substantial shift in the therapeutic landscape of AD. Moreover, natural products (NPs) have shown promise in AD drug research, with several currently under clinical investigation. Their distinct properties and mechanisms of action offer new avenues to complement and enhance existing AD treatment approaches. This review article aims to provide an overview of the recent advancements and prospects in AD therapeutics, focusing on both NPs and approved drugs.

Keywords

Alzheimer’s disease / amyloid-beta / Natural products / Clinical trials / Cognition

References

[1] Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025[J]. Alzheimers Res Ther, 2016, 8: 39.

[2] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies[J]. Cell, 2019, 179(2): 312-339.

[3] Ju Y, Tam KY. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease[J]. Neural Regen Res, 2022, 17(3): 543-549.

[4] Yiannopoulou KG, Anastasiou AI, Zachariou V, et al. Reasons for failed trials of disease-modifying treatments for Alzheimer disease and their contribution in recent research[J]. Biomedicines, 2019, 7(4): 97.

[5] Wang YL, You J, Cao JJ, et al. Screening of the ubiquitin-proteasome system activators for anti-Alzheimer’s disease by the high-content fluorescence imaging system[J]. Chin J Nat Med, 2022, 20(1): 33-42.

[6] Li Y, Zhao Y, Li X, et al. Biological and therapeutic role of LSD1 in Alzheimer’s diseases[J]. Front Pharmacol, 2022, 13: 1020556.

[7] Monteiro AR, Barbosa DJ, Remiao F, et al. Alzheimer’s disease: insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs[J]. Biochem Pharmacol, 2023, 211: 115522.

[8] Boxer AL, Sperling R. Accelerating Alzheimer’s therapeutic development: the past and future of clinical trials[J]. Cell, 2023, 186(22): 4757-4772.

[9] Cummings JL, Osse AML, Kinney JW. Alzheimer’s disease: novel targets and investigational drugs for disease modification[J]. Drugs, 2023, 83(15): 1387-1408.

[10] Se TE, Fauzi A, Tang YQ, et al. A review on advances of treatment modalities for Alzheimer’s disease[J]. Life Sci, 2021, 276: 119129.

[11] Conti Filho CE, Loss LB, Marcolongo-Pereira C, et al. Advances in Alzheimer’s disease’s pharmacological treatment[J]. Front Pharmacol, 2023, 14: 1101452.

[12] Huang LK, Kuan YC, Lin HW, et al. Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update [J]. J Biomed Sci, 2023, 30( 1): 83.

[13] Jin X, Guo JL, Wang L, et al. Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer’s disease: a comprehensive review[J]. Eur J Med Chem, 2021, 218: 113401.

[14] Kumar NS, Nisha N. Phytomedicines as potential inhibitors of β amyloid aggregation: significance to Alzheimer’s disease[J]. Chin J Nat Med, 2014, 12(11): 801-818.

[15] Selkoe DJ. The molecular pathology of Alzheimer’s disease[J]. Neuron, 1991, 6(4): 487-498.

[16] Hanger DP, Brion JP, Gallo JM, et al. Tau in Alzheimer’s disease and Down’s syndrome is insoluble and abnormally phosphorylated[J]. Biochem J, 1991, 275: 99-104.

[17] Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease[J]. Brain, 2018, 141(7): 1917-1933.

[18] Pinky PD, Pfitzer JC, Senfeld J, et al. Recent insights on glutamatergic dysfunction in Alzheimer’s disease and therapeutic implications[J]. Neuroscientist, 2023, 29(4): 461-471.

[19] Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer’s disease[J]. J Alzheimers Dis, 2017, 57(4): 1041-1048.

[20] Summers WK. Tacrine, and Alzheimer’s treatments[J]. J Alzheimers Dis, 2006, 9: 439-445.

[21] Qizilbash N, Birks J, Lopez AJ, et al. Tacrine for Alzheimer’s disease[J]. Cochrane Database Syst Rev, 2000, 1999(2): CD000202.

[22] Milelli A, De Simone A, Ticchi N, et al. Tacrine-based multifunctional agents in Alzheimer’s disease: an old story in continuous development section sign[J]. Curr Med Chem, 2017, 24(32): 3522-3546.

[23] Bubley A, Erofeev A, Gorelkin P, et al. Tacrine-based hybrids: past, present, and future[J]. Int J Mol Sci, 2023, 24(2): 1717.

[24] Noetzli M, Guidi M, Ebbing K, et al. Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance[J]. Brit J Clin Pharmaco, 2014, 78(1): 135-144.

[25] Wan LL, Guo C, Zhou ZY, et al. Steady-state plasma concentration of donepezil enantiomers and its stereoselective metabolism and transport in vitro[J]. Chirality, 2013, 25(9): 498-505.

[26] Yang YH, Wu SL, Chou MC, et al. Plasma concentration of donepezil to the therapeutic response of Alzheimer’s disease in Taiwanese[J]. J Alzheimers Dis, 2011, 23(3): 391-397.

[27] Matsui K, Oda Y, Nakata H, et al. Simultaneous determination of donepezil (aricept) enantiomers in human plasma by liquid chromatography-electrospray tandem mass spectrometry[J]. J Chromatogr B Biomed Sci Appl, 1999, 729(1-2): 147-155.

[28] Mohsin NU, Ahmad M. Donepezil: a review of the recent structural modifications and their impact on anti-Alzheimer activity[J]. Braz J Pharm Sci, 2020, 56: e18325.

[29] Hansen RA, Gartlehner G, Webb AP, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis[J]. Clin Interv Aging, 2008, 3(2): 211-225.

[30] Ray B, Maloney B, Sambamurti K, et al. Rivastigmine modifies the alpha-secretase pathway and potentially early Alzheimer’s disease[J]. Transl Psychiatry, 2020, 10(1): 47.

[31] Vicente-Zurdo D, Rosales-Conrado N, Leon-Gonzalez ME, et al. Novel rivastigmine derivatives as promising multi-target compounds for potential treatment of Alzheimer’s disease[J]. Biomedicines, 2022, 10(7): 1510.

[32] Gayke M, Hirapara N, Narode H, et al. Zinc chloride-catalyzed synthesis of carbamates: an application for the synthesis of the anti-Alzheimer’s drug rivastigmine[J]. ACS Omega, 2022, 7(40): 36017-36027.

[33] Arya A, Chahal R, Rao R, et al. Acetylcholinesterase inhibitory potential of various sesquiterpene analogues for Alzheimer’s disease therapy[J]. Biomolecules, 2021, 11(3): 350.

[34] Li J, Meng X, Li F, et al. Huperzine A combined with hyperbaric oxygen on the effect on cognitive function and serum hypoxia-inducible factor-1alpha Level in elderly patients with vascular dementia[J]. Am J Transl Res, 2021, 13(6): 6897-6904.

[35] Mei Z, Zheng P, Tan X, et al. Huperzine A alleviates neuroinflammation, oxidative stress and improves cognitive function after repetitive traumatic brain injury[J]. Metab Brain Dis, 2017, 32(6): 1861-1869.

[36] Peng Y, Lee DY, Jiang L, et al. Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695[J]. Neuroscience, 2007, 150(2): 386-395.

[37] Bullock R. Galantamine: use in Alzheimer’s disease and related disorders[J]. Expert Rev Neurother, 2004, 4(2): 153-163.

[38] Akk G, Steinbach JH. Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site[J]. J Neurosci, 2005, 25(8): 1992-2001.

[39] Sramek JJ, Frackiewicz EJ, Cutler NR. Review of the acetylcholinesterase inhibitor galanthamine[J]. Expert Opin Investig Drugs, 2000, 9(10): 2393-2402.

[40] Fan F, Liu H, Shi X, et al. The efficacy and safety of Alzheimer’s disease therapies: an updated umbrella review[J]. J Alzheimers Dis, 2022, 85(3): 1195-1204.

[41] Huang F, Fu Y. A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease, in healthy subjects and patients[J]. Curr Clin Pharmacol, 2010, 5(2): 115-124.

[42] Danysz W, Parsons CG, Mobius HJ, et al. Neuroprotective and symptomatological action of memantine relevant for Alzheimer’s disease-a unified glutamatergic hypothesis on the mechanism of action[J]. Neurotox Res, 2000, 2(2-3): 85-97.

[43] Kishi T, Matsunaga S, Oya K, et al. Memantine for Alzheimer’s disease: an updated systematic review and meta-analysis[J]. J Alzheimers Dis, 2017, 60(2): 401-425.

[44] Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease[J]. N Engl J Med, 2003, 348(14): 1333-1341.

[45] Molinuevo JL, Garcia-Gil V, Villar A. Memantine: an antiglutamatergic option for dementia[J]. Am J Alzheimers Dis Other Demen, 2004, 19(1): 10-18.

[46] Chen CM, Lin JK, Liu SH, et al. Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity[J]. J Neurosci Res, 2008, 86(12): 2696-2704.

[47] Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial[J]. JAMA, 2004, 291(3): 317-324.

[48] Gunawardena IPC, Retinasamy T, Shaikh MF. Is aducanumab for LMICs? Promises and challenges[J]. Brain Sci, 2021, 11(11): 1547.

[49] Dhillon S. Aducanumab: first approval[J]. Drugs, 2021, 81(12): 1437-1443.

[50] Selkoe DJ. Alzheimer disease and aducanumab: adjusting our approach[J]. Nat Rev Neurolt, 2019, 15(7): 365-366.

[51] Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility[J]. JAMA, 2021, 325(17): 1717-1718.

[52] Mallinckrodt C, Tian Y, Aisen PS, et al. Investigating partially discordant results in phase 3 studies of aducanumab[J]. J Prev Alzheimers Dis, 2023, 10(2): 171-177.

[53] Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease[J]. N Engl J Med, 2023, 388(1): 9-21.

[54] Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity[J]. Nat Rev Neurol, 2023, 19(3): 132-133.

[55] Wang X, Sun G, Feng T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression[J]. Cell Res, 2019, 29(10): 787-803.

[56] Agirman G, Hsiao EY. SnapShot: the microbiota-gut-brain axis[J]. Cell, 2021, 184(9): 2524-2524.

[57] Seo DO, Holtzman DM. Gut microbiota: from the forgotten organ to a potential key player in the pathology of Alzheimer’s disease[J]. J Gerontol A Biol Sci Med Sci, 2020, 75(7): 1232-1241.

[58] Ferreiro AL, Choi J, Ryou J, et al. Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease[J]. Sci Transl Med, 2023, 15(700): eabo2984.

[59] Panda SS, Jhanji N. Natural products as potential anti-Alzheimer agents[J]. Curr Med Chem, 2020, 27(35): 5887-5917.

[60] Gong Y, Wang S, Chen XB, et al. Utilizing natural products as new E3 ligase ligands for targeted protein degradation[J]. Chin J Nat Med, 2023, 21(12): 881-883.

[61] Wu F, Zhang R, Feng Q, et al. (-)-Clausenamide alleviated ER stress and apoptosis induced by OGD/R in primary neuron cultures[J]. Neurol Res, 2020, 42(9): 730-738.

[62] Kocis P, Tolar M, Yu J, et al. Elucidating the Abeta42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data [J]. CNS Drugs, 2017, 31(6): 495-509.

[63] Hey JA, Yu JY, Versavel M, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease[J]. Clin Pharmacokinet, 2018, 57(3): 315-333.

[64] Nemergut M, Marques SM, Uhrik L, et al. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s disease drug candidate[J]. Mol Neurodegener, 2023, 18(1): 38.

[65] Medina-Vera D, Lopez-Gambero AJ, Navarro JA, et al. Novel insights into D-Pinitol based therapies: a link between tau hyperphosphorylation and insulin resistance[J]. Neural Regen Res, 2024, 19(2): 289-295.

[66] Bu LJ, Yu HQ, Fan LL, et al. Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation[J]. World J Gastroenterol, 2017, 23(6): 986-998.

[67] Chen C, Yang C, Wang J, et al. Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer’s disease[J]. J Pineal Res, 2021, 71(4): e12774.

[68] Reading CL, Ahlem CN, Murphy MF. NM101 Phase III study of NE3107 in Alzheimer’s disease: rationale, design and therapeutic modulation of neuroinflammation and insulin resistance[J]. Neurodegener Dis Manag, 2021, 11(4): 289-298.

[69] Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer’s disease[J]. Ann N Y Acad Sci, 2017, 1403(1): 142-149.

[70] Cao C, Li Y, Liu H, et al. The potential therapeutic effects of THC on Alzheimer’s disease[J]. J Alzheimers Dis, 2014, 42(3): 973-984.

[71] Tian Z, Lu XT, Jiang X, et al. Bryostatin-1: a promising compound for neurological disorders[J]. Front Pharmacol, 2023, 14: 1187411.

[72] Alkon DL, Sun MK, Tuchman AJ, et al. Advanced Alzheimer’s disease patients show safe, significant, and persistent benefit in 6-month bryostatin trial[J]. J Alzheimers Dis, 2023, 96(2): 759-766.

Funding

Natural Science Foundations of Henan(232300420284)

Doctoral Research Start-up Fund Project of Shangqiu Normal University(7001/700224)

Key Cultivation Project of Shangqiu Normal University(4001/50032901)

National Natural Science Foundation of China(81971039)

Joint Research Fund of Science and Technology R&D Plan of Henan Province(222301420068)

Science and Technology Project for Tackling Key Problems of Henan province(232102311223)